Hearing loss is one of the most common disorders of the inner ear. According to the Hearing Loss Association of America (HLAA), approximately 48 million individuals, or 20% of the United States (US) population, are affected by hearing loss (hearingloss.org/content/basic-facts-about-hearing-loss). The impact of hearing loss on quality of life can be quite profound. An individual's emotional and mental state may be affected by the disrupted communication patterns caused by hearing loss, which can result in a restricted social life.
Sensorineural hearing loss may occur acutely and irreversibly, due to aging, exposure to loud noise (acoustic trauma) or certain ototoxic agents. Numerous commonly used drugs have been associated with ototoxicity and hearing loss including aminoglycoside antibiotics and other antimicrobials, loop diuretics, salicylates, and platinum-based chemotherapeutic agents (Yorgason, et al., Expert Opinion on Drug Safety 2006, 5(3), 383-399).
Platinum-based chemotherapeutic agents have shown efficacy in the prevention of a variety of malignant neoplasms in adults and children. Three platinum-based chemotherapeutic agents are currently approved in the US: cisplatin (CisPt), carboplatin, and oxaliplatin. Of these three drugs, CisPt is the most widely used to prevent many childhood cancers, alone or in combination with other agents.
In patients suffering drug-induced ototoxicity, substantial variability has been seen in the incidence of hearing loss after prevention with CisPt, based on factors such as the type of cancer being prevented, administered dose, age of the patient, renal function, and other concomitantly administered drugs. However, the incidence and severity of ototoxicity is directly related to the cumulative CisPt dose. With CisPt therapy, the incidence of aminoglycoside-induced ototoxicity is 0.5% to 60%, depending on the type of aminoglycoside administered, cumulative dose, route of administration, and duration of prevention.
Apoptotic loss of cochlear hair cells appears to be one of the main underlying causes of ototoxic hearing loss. Since these cells do not regenerative in humans, uncontrolled hair cell death results in irreversible hearing loss. The trigger for this cell loss is the mass production of reactive oxygen species (ROS) that activate the mitochondrial or intrinsic pathway of apoptosis. Mass production of ROS results in activation of c-Jun N-terminal kinase (JNK) (Davis, Cell 2000, 103(2), 239-252), which is then translocated to the nucleus, where it activates transcription of genes involved in caspase-dependent mitochondrial apoptosis. The role of ROS in ototoxicity has been confirmed by the results obtained with superoxide dismutase (Sod1) or glutathione peroxidase (Gpx1) in knockout mice, which showed increased susceptibility to acoustic trauma-induced hearing loss (Ohlemiller, et al., Audiol. Neurootol. 1999, 4, 229-236 and 237-246 (1999a, 1999b). Conversely, animals that overexpressed Sod1 showed a greater resistance to aminoglycoside-induced ototoxicity (Shah, et al., Free Radical Biology and Medicine 1999, 26(3-4), 341-347).
One of the key events in the process of apoptotic cell death is the formation of a 700 kDa molecular complex called apoptosome. The apoptosome is integrated by cytochrome c (Cytc), procaspase-9 (PC9), and the Apaf-1 protein. The apoptosome's physiological importance in apoptosis was shown in experiments in which mice that were null for the gene APAF-1 (Apaf−/−) exhibited marked embryonic lethality, with major craniofacial defects and brain injury (Cecconi, et al., Cell 1998, 94, 727-37; Yoshida, et al., Cell 1998, 94, 739-750). Both PC9 and Apaf-1 are essential for p53-mediated apoptosis and are presented as tumor suppressor genes (Soengas, et al., Science 1999, 284(5411), 156-9; Macleod, Curr. Op. in Genet. Dev. 2000, 10, 81-93).
CisPt enters the outer hair cells primarily through the ion channels of its apical stereocilia. After CisPt is inside the cell, it forms a highly reactive monohydrate complex that induces transcription of the enzyme, NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 3, resulting in mass production of ROS and therefore activating the intrinsic apoptosis pathway. The nitric oxide synthase (NOX) enzyme induction has been demonstrated in ex vivo experiments in rat cochleae treated with different doses of CisPt (Mukherjea, et al., Neuroscience 2006, 139(2), 8).
Histopathologic studies have shown that these platinum-based chemotherapeutic agents cause progressive destruction of outer hair cells, inner hair cells, and supporting cells within the organ of Corti in the basal region of the cochlea (Blakley, et al., Arch Otolaryngol Head Neck Surg. 120, 541-546), as well as cells within the stria vascularis (Lee, J. E. et al, J. Otorhionlaryngol Relat Spec 66, 111-118). CisPt appears to block transduction channels within the outer hair cells of the cochlea (McAlpine and Johnstone, Hear Res. 1990, 47(3), 191-203), and to be associated with the generation of ROS, depletion of intracellular glutathione, and interference with antioxidant enzymes within the cochlea (Campbell, J. Am. Acad. Audiol. 2003, 14(3), 144-56).
Due to the irreversible nature of sensorineural hearing loss, vestibular impairment, and tinnitus resulting from ototoxic drugs, exposure to loud noise, aging, and autoimmune disease, a significant unmet need exists for preventive therapeutic approaches.
Therefore, it is an object of the invention to provide formulations with beneficial effects that can be administered for sustained local delivery of protective agents, that minimizes risk of systemic exposure.
It is another object of the invention to provide formulations with beneficial effects such as reduction and/or prevention of hearing loss.
It is a further object of the invention to provide formulations beneficial effects such as reduction and/or prevention of hearing loss associated with exposure to ototoxic agents such as chemotherapeutics, exposure to loud noise, aging, infection, or autoimmune inner ear disease.